Evidence for a role of dipeptidyl peptidase IV in fibronectin-mediated interactions of hepatocytes with extracellular matrix

Abstract

Dipeptidyl peptidase IV (DPP IV) is a cell surface glycoprotein which has been implicated in hepatocyte-extracellular matrix interactions [Hixson, DeLourdes, Ponce, Allison & Walborg (1984) Exp. Cell Res. 152, 402-414; Walborg, Tsuchida, Weeden, Thomas, Barrick, McEntire, Allison & Hixson (1985) Exp. Cell Res. 158, 509-518; Hanski, Huhle & Reutter (1985) Biol. Chem. Hoppe-Seyler 366, 1169-1176]. However, its proteolytic substrate(s) and/or binding protein(s) which mediate this influence have not been conclusively identified. Nitrocellulose binding assays using 125I-labelled DPP IV that was purified to homogeneity from rat hepatocytes revealed a direct interaction of DPP IV with fibronectin. Although fibronectin could mediate an indirect binding of DPP IV to collagen, no evidence was found for a direct binding of DPP IV to native or denatured Type I collagen. Fibronectin appeared to bind DPP IV at a site distinct from its exopeptidase substrate recognition site since protease inhibitors such as competitive peptide substrates and phenylmethanesulphonyl fluoride enhanced binding, possibly as a result of an altered conformation of DPP IV. To determine if fibronectin binding to DPP IV is involved in the interaction of fibronectin with the hepatocyte surface, the effect of various DPP IV inhibitors on 125I-fibronectin binding to isolated hepatocytes in suspension was examined. Kinetic studies revealed that inhibitors of DPP IV which enhanced fibronectin binding in vitro accelerated the initial binding of fibronectin to the cell surface where it was subsequently cross-linked (presumably by tissue transglutaminase) to as yet undefined components. Immunolocalization of fibronectin and DPP IV in normal rat liver sections showed that both proteins were present along the hepatocyte sinusoidal membrane. These observations, coupled with previous results showing that DPP IV is tightly bound to biomatrix isolated from rat liver (Hixson et al., 1984; Walborg et al., 1985), suggest that DPP IV binding to fibronectin may play a role in interactions of hepatocytes with extracellular matrix in vivo and possibly in matrix assembly.

Biosynthesis and metabolism of dipeptidylpeptidase IV in primary cultured rat hepatocytes and Morris hepatoma 7777 cells

“…DPP IV from hepatocytes displayed a molecular mass of 105 kDa, in good accord with estimations performed by other laboratories for DPP IV from rat liver [II, 14,21,24,28]. The molecular mass of DPP IV isolated from MH 7777 cells was slightly lower (103 kDa) when separated by SDS/PAGE.…”

Dipeptidyl Peptidase Inhibits Malignant Phenotype of Prostate Cancer Cells by Blocking Basic Fibroblast Growth Factor Signaling Pathway

“…Disruption of these signaling events by DPPIV is probably involved in the assembly of fibronectin matrix and increase in cell adhesion that serves as a barrier for cell motility. This possibility is supported by data showing DPPIV binds to fibronectin and functions as an adhesion molecule (10), and that fibronectin on the cell surface disappears upon oncogenic transformation. Furthermore, overexpression of fibronectin leads to suppression of the transformed phenotype (49,50).…”

“…Its proteolytic activity leads to inactivation or degradation of these peptides (7,8). DPPIV is involved in diverse biological processes, including cell differentiation, adhesion, immunomodulation, and apoptosis, functions that are critical for controlling neoplastic transformation (7)(8)(9)(10)(11)(12)(13). DPPIV is expressed in normal epithelial cells and melanocytes (11)(12)(13)(14)(15).…”

Characterization of an established human hepatoma cell line constitutively expressing non-structural proteins of hepatitis C virus by transfection of viral cDNA

“…It is also a T cell activation antigen (Dang et al, 1990) and is directly associated with adenosine deaminase (Kameoka et al, 1993) or Tat of human immunodeficiency virus type 1 (Gutheil et al, 1994). Furthermore, DPP IV has been implicated in hepatocyte/extracellular matrix interaction (Piazza et al, 1989). Although the mechanism remains to be elucidated, it is intriguing that non-structural proteins of HCV expressed in this cell line may be associated with the high expression of CD26 which can mediate signal transduction of hepatocytes.…”